Until recently, myocardial loss and associated functional deterioration was regarded as irreversible. Yet, accumulating evidence suggests that injected stem cells can improve function of a failing heart, giving birth to a revolutionary concept of regenerative therapy for the heart. Bone marrow (BM)-derived mesenchymal stem cells (MSCs), known to differentiate into a wide variety of tissues, have shown in several preclinical models to result in improved myocardial function leading to a current human clinical trial to provide these dramatic new cell based therapies using human MSCs for myocardial repair. Hence, understanding how to enhance their therapeutic efficacy, e.g. to develop "super" stem cells, would expand their utility, especially in the elderly, patients with cardiac dysfunction, and in the diabetic population in whom stem cell dysfunction has been described. Using a strain that represents the upper end of the regenerative spectrum we isolated MSCs that demonstrate remarkably enhanced regenerative capacity as compared to those from C57Bl/6 (wildtype, WT) mice. The "super" MSCs demonstrated dramatically increased proliferation, vigorous wound tissue reconstitution, and vascular plasticity in a mouse granulation tissue model. Also, soluble factors derived from these cells caused significantly increased proliferation of fetal cardiomyoctyes and migration of endothelial cells over control conditioned media. In a murine myocardial infarct model, intramuscular peri- infarct injection of these cells showed favorable preliminary functional results over WT MSCs and control. We have identified a striking downregulation of the Wnt pathway in the "super" MSCs by differential expression of members of secreted frizzled related proteins and soluble Wnts as compared to WT. We verified both the relative downregulation of Wnt/-catenin signaling in MRLMSCs and that Wnt pathway inhibition enhanced MSC proliferation and granulation tissue formation, implicating this pathway as the molecular basis for the superior regenerative phenotype. We hypothesize that regulation of the Wnt signaling pathway is critical for MSC self-renewal and regenerative capacity. Moreover, we propose that modulating the activity of this pathway will recapitulate the "super stem cell" phenotype and is an excellent future target for cell based therapies for myocardial injuries and wound regeneration. [unreadable] [unreadable] [unreadable]